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Transcript of INSULIN -It is a peptide hormone consisting of 51 amino acids. -It is secreted by (β-cells of...
INSULIN
-It is a peptide hormone consisting of 51 amino acids.
-It is secreted by (β-cells of islets of Langerhans.
-It is secreted in the form of proinsulin which splits into insulin & C-peptide.
Actions:
- Carbohydrate metabolism; Hypoglycaemic effect"- Increases uptake & utilization of glucose by tissues.- Stimulates glycogenesis (in liver & muscles).- Stimulates lipogenesis (in liver & adipose tissue).- Inhibits gluconeogenesis & glycogenolysis.
- Fat metabolism;- Stimulates lipogenesis.- Inhibits lipolysis.-Inhibits ketogenesis.
-Protein metabolism: Anabolic effect.
- Electrolytes:- K: Intracellular shift.- Na: Aldosterone-like action (salt and water retention)
Regulation of secretion;- Stimulation: e.g. glucose, amino acids, sulphonylureas.- Inhibition: e.g. hypoglycaemia, hypokalaemia, somatostatin.Insulin deficiency or resistance: Results in disturbance of- Carbohydrate metabolism: "Hyperglycaemia"- Decreased uptake & utilization of glucose.- Decreased glycogenesis & lipogenesis.- Increased glycogenolysis & gluconeogenesis.
- Fat metabolism: "Hyperlipidaemia & Ketosis"- Decreased lipogenesis.- Increased lipolysis.- Increased ketogenesis.- Protein metabolism; "Catabolism"- Water & Electrolytes;- Osmotic diuresis due to gylcosuria.- Loss of K.
DIABETES MELLITUS
Definition:
A clinical syndrome characterized by disturbance of carbohydrate metabolism resulting from insulin deficiency or resistance or both & is characterized by "Hyperglycaemia".
Diabetes mellitus is the most common endocrine disease & its frequency is about 1-2% in most populations.
DIABETES MELLITUSAetiology;
I- Primary diabetes: ( > 95 % ) - Type I: Insulin-dependent diabetes mellitus (IDDM )- Previously termed juvenile-onset diabetes.- There is insulin deficiency due to damage of (β-cells).
- Factors that may play a role in the pathogenesis include:1- Genetic predisposition:- There is association with certain HLA types e.g. HLA-
DR3, DR4, B8, B15.- Incidence in identical twins is 50%.
DIABETES MELLITUS
2- Infectious agents: Viruses e.g. coxsackie B, rubella, mumps.
3- Immunological mechanisms;- Presence of pancreatic islet cell antibody
( PICA ).- May be associated with autoimmune
diseases.
DIABETES MELLITUS Primary diabetes - Type II: Non-insulin-
dependent diabetes mellitus (NIDDM).- Previously termed maturity-onset diabetes.- Insulin level is variable, usually increased in early
stages & decreased in late stages.- It results most probably from insulin resistance
which may be due to:• Insulin resistance at the receptor level.• Insulin resistance at the post-receptor level.• Increased anti-insulin hormones especially
glucagon.• Abnormal structure of insulin ( dysinsulinogenesis ).
DIABETES MELLITUS
• - Factors that may play a role in pathogenesis include:
1- Genetic predisposition:• No association with certain HLA types.• Incidence in identical twins is near 100%.• Maturity-onset diabetes of the young ( MODY )
is inherited as an autosomal dominant disorder.
DIABETES MELLITUS
2- Obesity; 80% of patients are obese.
DIABETES MELLITUS
• II- Secondary diabetes: ( < 5% )• 1- Pancreatic diseases;• Chronic pancreatitis, cystic fibrosis, cancer
pancreas, pancreatectomy, haemochromatosis.• 2- Endocrinal diseases:• - Cushing's syndrome, thyrotoxicosis.• - Pregnancy ( Gestational diabetes ).
DIABETES MELLITUS
• 3- Chronic liver failure.• 4- Drugs:• Corticosteroids, contraceptive pills,
thiazides, frusemide, diazoxide.• 5- Insulin receptor abnormalities.• 6- Genetic diseases: e.g.• Down's syndrome• 7- Malnutrition-related diabetes.
DIABETES MELLITUS
Type I diabetes
Type II diabetes
1- Incidence
< 1 0 %
> 90%
2- Age of onset
<30yr Usually 12-14
>40yr
3- Body weight
Usually underweight
Usually overweight
4- Severity
Severe
Mild or moderate
5- Stability
Unstable
Stable
6- Ketosis
Common
Very rare
7- Complications
More common
Less common
8- Insulin
Essential for therapy
Usually not required
9 - O ra l a n tid ia b e tic s
Of no effect
Effective
74
Comparison between type I & type II primary diabetes
Presentations of Diabetes
1 - Asymptomatic & accidentally discovered.
2- Classic symptoms:- Polyuria, polydipsia, polyphagia, pruritus
and parasthesias.- Loss of weight especially in IDDM.3- Diabetic complications.4- Diabetic coma.
COMPLICATIONS OF DIABETESI- Cardiovascular complications:1- Microangiopathy; ( Small vessel disease )- Affecting small blood vessels especially:• Vasa nervosa leading to neuropathy.• Glomeruli leading to nephropathy.• Retinal vessels leading to retinopathy.- There is thickening of basement membrane &
deposition of glycated proteins & lipids leading to:
• Increased vascular permeability.• Narrowing & occlusion of lumen with
neovascularization.
COMPLICATIONS OF DIABETES• 2- Atherosclerosis: ( Large vessel disease )
e.g. - Coronary heart disease:• Angina, infarction ( may be painless ), heart
failure, arrhythmias, sudden death.• - Cerebrovascular disease:.• - Peripheral vascular disease:• May cause manifestations of ischaemia e.g.
intermittent claudications & gangrene.• - Renovascular hypertension.• 3- Cardiomyopathy: May be due to small
vessel affection.• 4- Increased incidence of hypertension.
COMPLICATIONS OF DIABETES• II- Cutaneous complications:• 1- Pruritus:• Especially pruritus vulvae which may be
due to monilial infection, glycosuria, parasthesia or allergy to antidiabetic drugs.
• 2- Infections:• Multiple furuncles, carbuncles,
abscesses, cellulitis & fungal infections especially in anogenital & interdigital regions.
COMPLICATIONS OF DIABETES• 3- Necrobiosis lipoidica diabeticorum; • • Painless papules formed of central
yellowish area surrounded by brownish border.
• • Usually occur over the anterior surfaces of the legs.
• • Ulceration may occur.• 4- Diabetic dermopathy:• • Painless reddish papules.• • Usually occur over the shins ( shin spots ).• • May heal leaving a scar.
COMPLICATIONS OF DIABETES5- Xanthomata: due to hyperlipidaemia.
6- Skin abnormalities of diabetic foot:7- Delayed healing of wounds.8- In IDDM: tight waxy skin over the dorsum of fingers & hands.9- Complications of treatment: e.g.• Insulin lipodystrophy or insulin hypertrophy.• Skin rash with sulphonylureas.10-Interdiqital Fungal Infection
COMPLICATIONS OF DIABETES
COMPLICATIONS OF DIABETES• III- Neurological Complications: • A- Cerebral:• 1- Coma of different types:• 2- Cerebral atherosclerosis & thrombosis• 3- Fungal infections• B- Spinal cord: ( rare )
COMPLICATIONS OF DIABETESC- Radiculopathy:• Presenting with pain, parasthesias, sensory
loss, weakness & wasting.• Roots of sciatic nerve are especially affected. D- Neuropathy; peripheral , autonomic. E- Diabetic amyotrophy• There are weakness & wasting of proximal
muscles of pelvis & front of the thigh ( quadriceps ).
• May be associated with pain & sensory loss.
COMPLICATIONS OF DIABETES• IV- Ocular Complications:• 1- Diabetic retinopathy:• • Proliferative retinopathy, which may lead to
retinal detachment & vitreous haemorrhage.
COMPLICATIONS OF DIABETES
COMPLICATIONS OF DIABETES
• 2- Diabetic cataract.• 3- glaucoma.• 4- Errors of refraction.• 5- Ocular infections e.g. blepharitis & panophthalmitis.• 6- Neurological complications of the eye: e.g.• - Paralysis of ocular nerves especially oculomotor nerve.• - Rarely Argyl-Robertson pupil. bilateral small pupils that
constrict when the patient focuses on a near object (they “accommodate”), but do not constrict when exposed to bright light (they do not “react” to light).
COMPLICATIONS OF DIABETES
• V- Urinary Complications:• 1- Urinary tract infections:• - Pyelonephritis• - Cystitis, urethritis & pyelitis.• 2- Diabetic Nephropathy:
COMPLICATIONS OF DIABETES• - Clinical Picture:• 1 - Long-standing diabetes.• 2- Proteinuria:• - Microalbuminuria followed by• - Macroproteinuria followed by• - Heavy proteinuria & nephrotic syndrome.• 3- Hypertension.• 4- Lately, chronic renal failure.• 5- Diabetic retinopathy & neuropathy are usually present.
COMPLICATIONS OF DIABETES• VI- Respiratory Complications:• 1- Pulmonary infections especially tuberculosis.• 2- During ketosis: Kussmaul's breathing & acetone odour.
• VII- Gastrointestinal Compilations:• 1- Dry beefy tongue.• 2- Loosening of teeth.• 3- Delayed gastric emptying• 4- During ketosis: nausea, vomiting, abdominal pain & may be
haematemesis.• 5- Diarrhea: usually nocturnal & may be malabsorption due to bacterial
overgrowth.• 6- Constipation.• 7- Fatty liver.• 8- Gallstones & chronic cholecystitis.• 9- Pancreatitis.
COMPLICATIONS OF DIABETES
VIII- Genital Complications:• A- In males: Impotence & loss of testicular
sensation. • B- In females:• 1- Gynaecological:• - Pruritus vulvae.• - Infections e.g. vaginal moniliasis.
COMPLICATIONS OF DIABETES2- Obstetric:• A- Effects of diabetes on pregnancy:• - The mother:• Increased incidence of toxaemia, hypertension, hydramnios &
placental dysfunction.• - The fetus:• • Large birth weight.• • Congenital anomalies• • Neonatal hypoglycaemia.• • Respiratory distress syndrome.• • Increased incidence of abortion, premature labor, stillbirth &
neonatal death.
COMPLICATIONS OF DIABETESIX - Diabetic Foot;• • It results from the combined effect of:• - Vascular insufficiency (atherosclerosis & microangiopathy).• - Neuropathy (sensory, autonomic & motor).• - Infections.• • It includes the following manifestations:• - Features of ischaemia e.g. intermittent claudications & may
end into gangrene. Trophic changes especially trophic ulcers & Charcot's arthropathy.
• - Features of neuropathy.• - Infections.
COMPLICATIONS OF DIABETES
COMPLICATIONS OF DIABETES
X- Joint Complication:• • Osteoarthrosis.• • Increased incidence of gouty arthropathy.• • Charcot's arthropathy.
COMA IN DIABETES
1) Diabetic Ketoacidosis;• - Pathogenesis:• • It occurs in IDDM.• • There is severe insulin deficiency leading to:• - Severe hyperglycaemia.• - Lipolysis & Ketogenesis i.e. production of
ketone bodies including acetoacetic acid & (β-hydroxybutyric acid.
COMA IN DIABETES • • These abnormalities lead to:• - Increased excretion of glucose & ketoacids in
urine leading to marked polyuria & dehydration.• - Metabolic acidosis.• - Electrolyte disturbances.• - Coma due to the combined effect of ketone
bodies, acidosis, dehydration & electrolyte disturbances.
COMA IN DIABETES
• - Precipitating factors:• 1 - Infections.• 2- Trauma & surgery.• 3- Severe physical & emotional stress.• 4- Myocardial infarction & cerebrovascular stroke.• 5- Pregnancy & labour.• 6- Starvation.• 7- Severe vomiting.• 8- Inadequate treatment.
COMA IN DIABETES Clinical Picture:• 1- Gradual onset with marked polyuria & polydipsia.• 2- Anorexia, nausea, vomiting, abdominal pain & may
be haematemesis.• 3- Kussmaul's ( acidotic ) breathing & acetone odour
of breath.• 4- Signs of dehydration: dry tongue & skin, sunken
eyes & decreased skin turgor.• 5- Signs of volume depletion: rapid week pulse & low
BP. • 6- Deterioration of consciousness & coma.
COMA IN DIABETES
Investigations:• • Urine analysis: positive for glucose & ketones.• • High blood glucose level.• • Serum K: normal or high despite depletion of
body K due to extracellular shift.• • Decreased pH & HCO3.
COMA IN DIABETES 2) Hypoglycaemic coma: - Precipitating factors:• It may occur due to overdosage of insulin or sulphonylureas, missed meal or
performing unusual exercise.Clinical Picture;
• 1- Sudden onset with irritability, tremors, pallor, sweating, tachycardia & palpitation.
• 2- Arrhythmias & precipitation of angina.• 3- Rapid full pulse & dilated pupils.• 4- Hyperreflexia & may be extensor plantar reflex.• 5- Convulsions & coma.• 6- Brain damage & death in severe prolonged cases.• 7- Rapid improvement with IV glucose.
Investigations:• • Urine analysis: no glucose.• • Blood glucose level: low ( usually < 45 mg/dl).
COMA IN DIABETES
• 3) Hyperosmolar non-ketotic coma:• - Pathogenesis:• • It occurs in NIDDM.• • There is insulin deficiency leading to marked
hyperglycaemia but without ketosis.• • Osmotic diuresis leads to dehydration with
high serum glucose & Na (increased plasma osmolality ).
COMA IN DIABETES
- Clinical Picture:• 1 - Gradual onset with marked polyuria &
polydipsia.• 2- Signs of dehydration: dry tongue & skin,
sunken eyes & decreased skin turgor.• 3- Signs of volume depletion: rapid week pulse
& low BP.• 4- Deterioration of consciousness & coma.
COMA IN DIABETES
- Investigations:• • Urine analysis: glucose without ketone
bodies.• • Very high blood glucose level.• • High serum Na.• • Increased plasma osmolality.
COMA IN DIABETES 4) Lactic acidosis;• - Precipitating factors;• • It may be precipitated by:• - Tissue hypoxia e.g. shock, heart failure, respiratory
failure.• - Biguanides.• - Alcohol.• • There is anaerobic glycolysis with production of
lactic acid leading to severe acidosis.
COMA IN DIABETES
Clinical picture:• 1- Kussmaul's ( acidotic ) breathing.• 2- Deterioration of consciousness & coma.
Investigations:• • Decreased pH & HCO3.• • Increased plasma lactate.• • Increased anion gap.
COMA IN DIABETES
5) Other causes of coma in diabetics;• • Uraemic coma in patients with diabetic
nephropathy.• • Cerebral thrombosis on top of atherosclerosis.• • Cerebral mucormycosis.• • Associated causes of coma.
INVESTIGATIONS OF DIABETES1- Plasma glucose level: ( Fasting & 2 hours post-prandial)• - Normal levels:• -Fasting: 70-110 mg/dl.• - 2 hours post-prandial: less than 140 mg/dl.
• - Diagnosis of diabetes:• - Fasting: > 140 mg/dl ( on at least 2 occasions ).• - 2 hours post-prandial ( after ingestion of 75 gm glucose ):
> 200 mg/dl ( and at least one other occasion ).• - Recently, diabetes is diagnosed if fasting glucose > 126 mg/dl
( on at least 2 occasions).• - Levels between those of normal individuals & diabetics are termed
"impaired glucose tolerance“.
INVESTIGATIONS OF DIABETES
2- Urine analysis:• - For glucose:• Using strips• - For ketone bodies:• Using strips5- Monitoring of treatment of diabetes;• Plasma glucose monitoring. .
INVESTIGATIONS OF DIABETES
INVESTIGATIONS OF DIABETES
• Glycated haemoglobin ( glycosylated haemoglobin, HbA1C)
• - It is formed by linkage of glucose to (3-chains of HbA.
• - Its measurement estimates the diabetic control in the preceding several weeks (6-12 weeks ).
• - Its normal level: 6-8% of total haemoglobin.
INVESTIGATIONS OF DIABETES
6- Investigations for complications: e.g.• • Urine analysis including proteins & test for
microalbuminuria.• • Renal function tests & renal imaging.• • Plasma lipids.• •ECG.
7- Investigations for the cause: only if secondary diabetes is suspected.
TREATMENT OF DIABETES
• 1-Diet.• 2- Oral antidiabetic drugs.• 3- Insulin.• 4- General measures.• 5- Treatment of complications.• 6- Treatment of different types of coma.• 7- In secondary diabetes: treatment of the cause.• 8- New lines of treatment.
TREATMENT OF DIABETES
2) Oral anti-diabetic ( hypoglycaemic ) drugs: A- Sulphonylureas:
Preparations:Drug
Dose
Tolutamide (Rastinon)
500mg t.d.s.
Acetohexamide (Dimelor)
500mg/12hr
Chlorpropamide (Diabenase)
100-5 00 mg/d
Glibenclamide (Daonil)
5-15mg/d
Gliclazide (Diamicron)
80- 120 mg/d
Glipizide (Minidiab)
2.5-30 mg/d
Glimipride (Amaryl)
1-3 mg/d
TREATMENT OF DIABETES
B- Biguanides:- Indications:• NIDDM not controlled by diet alone especially
in obese patients.
- Preparations:• 1- Metformin ( Glucophage ): 500 mg t.d.s.• 2- Phenformin (Insoral ): 25 mg t.d.s. ( of no use
now ).
TREATMENT OF DIABETES
3) Insulin:- Indications:
• 1-IDDM.• 2- Severe NIDDM not controlled by diet & oral
hypoglycaemic drugs.• 3- During pregnancy.• 4- Diabetic ketosis & hyperosmolar coma.• 5- Severe stress e.g. infection, surgery.
TREATMENT OF DIABETES
Preparations:
Onset of
Peak of
Duration of
Action (hr)
Action (hr)
Action (hr) 1 - S h o rt ac tin g : e .g .
- Crystalline ( Regular )
0.5
3
6 - Semilente
1
6
12 2 - In te rm e d ia te a c tin g : e .g .
- Isophane ( NPH )
3
8
24 - Lente
3
8
24 3- Long acting: e.g.
- Protamine zink insulin (PZI)
4
16
36 - Ultralente
4
16
36
TREATMENT OF DIABETES
5) General measures:• 1- Regular physical exercise.• 2- Avoidance of smoking & alcohol.• 3- Multivitamins especially vitamin
B complex.
6) Treatment of diabetic complications